Tranquilizers

ABSTRACT

1. COMPOUNDS CORRESPONDING TO THE FORMULA   R-1,4-PHENYLENE-CH=N-C(-R1)(-R2)-CH2-OOC-R3   WHERE R IS HYDROGEN, CHLORINE OR METHOXY, R1 AND R2 ARE HYDROGEN OR METHYL AND ARE THE SAME OR DIFFERENT, AND R3 IS METHYL OR ETHYL.

United States Patent O ifice 3,839,422 TRANQUILIZERS Herbert L. Wehrmeister, Terre Haute, Ind., assignor to Commercial Solvents Corporation No Drawing. Filed Dec. 4, 1972, Ser. No. 312,089 Int. 'Cl. C07c 119/10 US. Cl. 260-490 11 Claims ABSTRACT OF THE DISCLOSURE Compounds corresponding to the formula where R is hydrogen, chlorine or methoxy; R and R are hydrogen or methyl and can be the same or different; and R can be methyl or ethyl. The compounds have utility as tranquilizing agents for animals.

SUMMARY OF THE INVENTION This invention relates to compounds known as Schiif bases. In a particular aspect this invention relates to Schilf bases useful as tranquilizing agents for animals.

Schiff bases have long been known. Previously they have been prepared by reacting an aldehyde with a primary amine:

Nm omono @awonom H2O where R is hydrogen, chlorine or methoxy, R and R are hydrogen or methyl and can be the same or different, and R can be methyl or ethyl, have a calming or tranquilizing effect on animals when administered orally or intravenously. The compounds are prepared by reacting an aldehyde corresponding to the formula with an oxazoline corresponding to the formula preferably but not necessarily in the presence of -a trace of an acid catalyst, at a temperature of from about room temperature to about 160.

Patented Oct. 1, 1974 DETAILED DISCUSSION It was very surprising to discover that aldehydes react with a 2-alkyl-2-oxazoline to produce a Schiff base because previously the prior art had taught that the aldehyde would condense with the a-carbon attached to the carbon atom in the 2-position and form an unsaturated linkage therewith (Wehrmeister, US. Pat. 3,466,308).

The compounds of this invention are prepared by reacting the aldehyde and the oxazoline in about a 1:1 mole ratio, preferably in the presence of an inert solvent, e.g. xylene. Reaction times of two days at 140-160 or up to twelve days or more at room temperature are required for good yields.

Suitable acid catalysts include organic and inorganic catalysts and include inorganic mineral acids such as sulphuric, hydrochloric and phosphoric acids; organic carboxylic and sulphonic acids, such as formic, benzene sulphonic, p-xylenesulphonic, p-toluenesulphonic, naphthalenesulphonic acids and trifiuoroacetic acid. Trifluoroacetic acid has been found to be advantageous as a catalyst. The amount of catalyst employed will generally range from about 0.001 to 10%, preferably from about 0.05 to about 1.0% by weight of the reactants, although more or less can be employed. A catalyst is not necessary, but is preferred because it shortens the reaction time.

The aldehydes and oxazolines corresponding to the foregoing formula which are useful in the practice of this invention are commercially available and the usual commercial materials are suitable.

The compounds of this invention have demonstrated pharmacological activity. -In particular they have been found to exert a depressant action on the central nervous system when tested under standard and accepted pharmacological procedures in laboratory animals, such as mice. They are, therefore, deemed to possess utility in experimental and comparative pharmacology and are of value to treat conditions in animals, such as mice, rats and the like, responsive to treatment with central nervous system depressant agents, such as the need to induce a calming effect.

These compounds are weakly alkaline and readily form salts with most acids. Many of these salts are watersoluble and advantageously can be used for administering these compounds. The invention therefore contemplates the administration of pharmaceutically acceptable salts of the disclosed compounds as well as the unneutralized compounds themselves.

The compounds of this invention may be administered alone or in combination with other pharmacologicallyactive ingredients. Whether singly or in combination, they may be used in compositions for oral administration combined, if desired, with extenders or carriers which are relatively non-toxic or inert. 0n the other hand, they may be administered in liquid form as a suspension or solution in a suitable vehicle for parenteral use.

The invention will be better understood with reference to the following examples. It is understood, however, that the examples are intended for illustration only and it is not intended that the invention be limited thereby.

EXAMPLE 1 p-Anisaldehyde 68.1 g. (0.5 mole), 2-methyl-2-oxazoline 85.2 g. (1.0 mole) and sodium bisulfate 2 g. were mixed with ml. of xylene in a 500 ml. round-bottom flask connected with a 4-bulb Snyder column, water separator and reflux condenser. The mixture was allowed to react overnight with stirring. The mixture was then heated at a temperature of about l32-160 C. for about eight hours, and after cooling was filtered. The filtrate was distilled through a -inch Vigreux column.-The fraction distilling at 124-132 at 0.1 mm. analyzed: carbon 64.96%; hydrogen 6.70%; nitrogen 6.76%!. These values were in good agreement with calculated values for the proposed structure: carbon 65.12%, hydrogen 6.83%; and nitrogen 6.33%. This fraction was redistilled and the cut distilling at l28130 at 0.08 mm. was taken as the pure product.

The nuclear magnetic resonance (NMR) spectrum and infra-red absorption spectrum were consistent with the proposed structure:

When administered orally to laboratory mice, the LD was determined to be 1050 mg./kg. the LD was 1975:160 and the LD was 4200 mg./kg. A trained observer determined that animals receiving it were tranquilized.

EXAMPLE 2 p-Chlorobenzaldehyde 28.1 g. (0.2 mole) and 2-ethyl- 2-oxazoline 0. g. (0.2 mole) were charged to a flask mixed and allowed to stand at room temperature for 22 days. The mixture was distilled through an 8 inch Vigreux column and the fraction distilling at 128 at 0.12 mm. to 136 at 0.3 mm. to 144 at 0.7 mm. was selected as the product. It analyzed: carbon 60.63%; hydrogen 6.09%; chlorine 14.67% and nitrogen 6.05%. These values were in good agreement with calculated values for the proposed structure: carbon 60.13%; hydrogen 5.89%; chlorine 14.79% and nitrogen 5.84%. The NMR spectrum was consistent with the proposed structure The LD by oral administration to mice was 1150 ing/kg. The LD was 2100-3200 and the LD 'Was 2800 mg./kg. A trained observer determined that the animals receiving it were tranquilized.

EXAMPLE 3 The experiment of Example 1 was repeated in all essential details except that benzaldehyde 10. 6 g. (0.1 mole) was reacted with 2-methyl-2-oxazoline 8.5 (0.1 mole), but without added sodium bisulfate catalyst, over a period of eleven days at room temperature. The mixture was distilled through an 8" Vigreux column and the fraction distilling at 126-129 at 5 mm. was selected as the prodnet. The NMR spectrum and the infra-red absorption spectrum were consistent with the proposed structure:

The compound analyzed as follows: carbon 68.21%; hydrogen 7.19%; nitrogen 7.51%. These values were in fair agreement with calculated values for the proposed structure: carbon 69.10%; hydrogen 6.85%; and nitrogen 7.33%. The unsaturated linkage was catalytically reduced and the ester group was hydrolyzed to yield a known compound, benzylaminoethanol, b.p. 156 (17 mm.). The picrate was prepared, mp. 135-136 which agrees with published values, thus proving the proposed Schiif base structure.

The LD by oral administration to mice was 2200: 160 ing/kg. The LD was 1700 mg./kg. and the LD- was about 2800. A trained observer determined that animals receiving the compound were tranquilized.

EXAMPLE 4 The experiment of Example 3 was repeated in all essential details except that the oxazoline used was 2-ethyl- 2-oxazoline 10 g. (0.1 mole). The mi ture was allowed to stand at room temperature, and after about six days, one drop of trifiuoroacetic acid was added as a catalyst. After standing another 16 days, the mixture was distilled through an 8" Vigreux column. The fraction distilling at 137- 138 C. at 5 mm. was taken as the product. The NMR spectrum and infra-red spectrum were consistent with the structure:

EXAMPLE 5 The experiment of Example 4 was repeated in all essential details except that the oxazoline used was 2-ethyl-4- methyl-2-oxazoline and the trifiuoroacetic acid was added on the seventh day. After standing an additional 16 days at room temperature, the mixture was distilled through an 8" Vigreux column. The fraction distilling at 136- 138 and 5 mm. was taken as the product. The NMR spectrum and infrared absorption spectrum were consistent with the structure:

The product analyzed: C, 70.61%; H, 8.16; N, 6.58. Calculated values for the above structure is: C, 71.19%; H, 7.82; N, 6.39.

The product had a LD by oral administration to white mice of approximately 3900 mg./kg. The LD was 1700 mg./kg. and the LD was greater than 5000 mg./kg. A trained observer determined that animals receiving the compound were tranquilized.

EXAMPLE 6 The experiment of Example 4 was repeated in all essential details except that the oxazoline was 2,4,4-trimethy1- 2-oxazoline, 11.6 g. and the trifiuoroacetic acid was added after about 2 days. After an additional 16 days, the crystals which had separated were dissolved by adding 25 ml. benzene and warming. The solution was then chilled for 3 days and the precipitate was separated by filtration and washed with benzene. The filtrate was distilled through an 8" Vigreux column and the fraction distilling at 133 at 5 mm. was selected as the product. The NMR spectrum and infra-red absorption spectrum were consistent for a compound having the structure Y It analyzed: c, 70.35%; H, 7.65; and N, 6.68.

where R is hydrogen, chlorine or methoxy, R and R are hydrogen or methyl and are the same or difierent, and R is methyl or ethyl.

2. The compounds of claim 1 wherein R and R are hydrogen.

3. The compounds of claim 1 'wherein R} and R are methyl.

4. The compounds of claim 1 wherein R is methyl and R is hydrogen.

5. The compound of claim 1 wherein R is methyl.

6. The compound of claim 1 wherein R is ethyl.

7. The compound of claim 1 wherein R is hydrogen.

8. The compound of claim 1 wherein R is chlorine.

9. The compound of claim 1 wherein R is methoxy.

10. A process for the preparation of the compounds of the formula where R is hydrogen, chlorine or methoxy; R and R are hydrogen or methyl and are the same or diiferent, and R is methyl or ethyl comprising reacting in about a 1:1 mole ratio an aldehyde represented by the formula where R is hydrogen, chlorine or methoxy, with an oxazoline represented by the formula R2 N 5 R RLC/ O-CHz where R and R are hydrogen or methyl and are the same or diiferent and R is methyl or ethyl at a temperature of from about room temperature to about and recovering said compound.

11. The process of claim 10 wherein the reaction is elfected in the presence of from about 0.05 to about 1.0% based on the weight of the reactants of an acid catalyst selected from the group consisting of mineral acids, benzene sulfonic acid, p-xylene sulfonic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, formic acid and trifluoroacetic acid.

References Cited Chem. Abstracts, 58:1551h. Chem. Abstracts, 62:5751b. Chem. Abstracts, 68:58639k.

VIVIAN GARNER, Primary Examiner US. Cl. X.R.

mg?" 'UNITEDS IATES PATENT OFFICE I CERTIFICATE OF CORRECTION v Patent No. I; 1 422 Dated oetqaer l, 1974 Q )figrbg rt L. Wehicmeister I 7 It is certified that: error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown lzvelow} Column 1, line '48 i zh at po rtion qf the formula reading 7 -CN=N- should read -CH=N i ne and sealed. 'this 29th day 'of April 197s.";

(s eALi e c. MARSHALL DANN RUTH C, MASON I 7 Commissioner of lfatents Attesting Officer Y e1 fnd Trademar ks 

1. COMPOUNDS CORRESPONDING TO THE FORMULA 